PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy

Liu, Jinhua; Chen, Zichao; Li, Yaqun; Zhao, Wenjie; Wu, Jibiao; Zhang, Zhen

doi:10.3389/fphar.2021.731798

Cited by 207 publications

(198 citation statements)

References 102 publications

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“…Furthermore, the overexpression of PD-L1 is correlated with poor prognosis in many cancers (291)(292)(293)(294). In order to block the interaction between PD-1 and PD-L1, various mAbs, such as nivolumab, pembrolizumab, avelumab, lambrolizumab, and atezolizumab, have been developed (295). After encouraging results from different clinical trials, the FDA granted accelerated approval to nivolumab for the treatment of advanced melanoma in 2014 (296), and advanced squamous NSCLC in 2015 (297).…”

Section: Overcoming Inhibition By Negative Immune Checkpointsmentioning

confidence: 99%

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

et al. 2022

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During this last decade, adoptive transfer of T lymphocytes genetically modified to express chimeric antigen receptors (CARs) emerged as a valuable therapeutic strategy in hematological cancers. However, this immunotherapy has demonstrated limited efficacy in solid tumors. The main obstacle encountered by CAR-T cells in solid malignancies is the immunosuppressive tumor microenvironment (TME). The TME impedes tumor trafficking and penetration of T lymphocytes and installs an immunosuppressive milieu by producing suppressive soluble factors and by overexpressing negative immune checkpoints. In order to overcome these hurdles, new CAR-T cells engineering strategies were designed, to potentiate tumor recognition and infiltration and anti-cancer activity in the hostile TME. In this review, we provide an overview of the major mechanisms used by tumor cells to evade immune defenses and we critically expose the most optimistic engineering strategies to make CAR-T cell therapy a solid option for solid tumors.

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Section: Overcoming Inhibition By Negative Immune Checkpointsmentioning

confidence: 99%

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

et al. 2022

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“…This interaction inhibits CD4+/CD8+ tumor-infiltrating T-lymphocytes (CD4+/CD8+ TILs), which results in a decrease in cytokines, such as Interleucin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor (TNF). PD-L1 on the surface of tumor cells can be enhanced by IFN-γ produced by activated T-cells [ 10 ]. PD-L1 expression is upregulated through signaling pathways, including PI3K/Akt/mTOR and PD-L1-mediated immunoresistance could be suppressed by PI3K kinase pathway inhibitors.…”

Section: Immune Checkpoint Expression In Connection With Clinical Features and The Therapeutic Efficacy Of Their Inhibitionmentioning

confidence: 99%

Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis

et al. 2021

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To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival.

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“…Monoclonal antibodies (mAbs) targeting critical immune checkpoints, such as PD-1/PD-L1 and CTLA-4, have significantly ameliorated the treatment of advanced solid tumors, such as lung (NSCLC), skin and liver cancers. Immune checkpoint inhibitors targeting and blocking the interaction of certain cell surface proteins, such as PD-1 expressed on diverse immune cells or PD-L1 expressed on cancer cells, act as brakes on immune responses [ 40 , 41 ]. A handful of mAbs directed against PD-1 or PD-L1 have been approved for cancer treatment, including pembrolizumab, nivolumab, atezolizumab, camrelizumab and others.…”

Section: The Tim-3 Immune Checkpoint and Its Targeting With Antibodiesmentioning

confidence: 99%

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

Bailly

Thuru

Quesnel

2021

Cancers

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The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient.

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PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy

Cited by 207 publications

References 102 publications

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

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